The rapid development of high-throughput sequencing in recent years has facilitated great progress in the molecular-targeted therapy of hematological malignancies, including leukemia, lymphoma, and multiple myeloma. BCL-2 inhibitors are among the most important molecular-targeted agents. Immunotherapy for hematologic malignancy has rapidly increased in popularity in recent years and has been proven to improve the overall survival rate. However, few clinical studies have investigated combination therapy with BCL-2 inhibitors and immunotherapies, such as immune molecule-targeted drugs or immune cell adoptive therapy. In this review, we discuss the drug discovery process, current clinical application status, and resistance and tolerance issues associated with BCL-2 inhibitors. We emphasize their important role in regulating the immune system and propose that the combination of BCL-2 inhibitors with immunotherapy may be one of the most promising treatment methods for hematologic malignancies.

BACKGROUND: Psoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs.
OBJECTIVE: To investigate the role of senescent CD4+ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis.
METHODS: We explored the expression levels of p16INK4a and p21, classical markers of cellular senescence, in CD4+ T cells from human psoriatic lesions and imiquimod (IMQ)-induced psoriatic lesions. We prepared a senolytic gel using B-cell lymphoma 2 (BCL-2) inhibitor ABT-737 and evaluated its therapeutic efficacy in treating psoriasis.
RESULTS: Using multispectrum immunohistochemistry (mIHC) staining, we detected increased expression levels of p16INK4a and p21 in CD4+ T cells from psoriatic lesions. After topical application of ABT-737 gel, significant alleviation of IMQ-induced psoriatic lesions was observed, with milder pathological alterations. Mechanistically, ABT-737 gel significantly decreased the percentage of senescent cells, expression of T cell receptor (TCR) α and β chains, and expression of Tet methylcytosine dioxygenase 2 (Tet2) in IMQ-induced psoriatic lesions, as determined by mIHC, high-throughput sequencing of the TCR repertoire, and RT-qPCR, respectively. Furthermore, the severity of psoriatic lesions in CD4creTet2f/f mice was milder than that in Tet2f/f mice in the IMQ-induced psoriasis model.
CONCLUSIONS: We revealed the roles of senescent CD4+ T cells in developing psoriasis and highlighted the therapeutic potential of topical ABT-737 gel in treating psoriasis through the elimination of senescent cells, modulation of the TCR αβ repertoire, and regulation of the TET2-Th17 cell pathway.

Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors of pharmacokinetics in hematologic malignancies. This review described PPK models of VEN examining the magnitude and types of covariate effects in PK parameters, as well as identified areas that require further investigation in order to facilitate their use. Currently, there are six analyses on PPK models of VEN summarized in this review. Most analyses described the pharmacokinetics of VEN with a two-compartment model and all covariates are categorical. The median estimated apparent clearance (CL/F) was 446 L/Day and apparent volume of distribution of the central compartment (V2/F) was 114.5 L. The median IIV of CL/F reported was 39.5% and V2/F was 46.7%. Most commonly, CYP3A inhibitors, OATP1B3 inhibitors and rituximab co-administration were found to be significant covariates on CL/F. In addition, sex and population were influential covariates on V2/F. A detailed description of the characteristics of PPK models of VEN is provided in this review, as well as the effects of covariates on the PK parameters. For future development of the VEN PPK model, CYP3A inhibitors, rituximab co-administration, OATP1B1 transporter inhibitors, sex, population, and food might be considered. Further research and comprehensive investigations should be undertaken to explore reference ranges for therapeutic drug monitoring, define the potential role of patients with cerebrospinal fluid complications, and assess new or potential covariates. These endeavors will facilitate the development of personalized VEN therapy.

Targeting the intrinsic apoptotic pathway regulated by B-cell lymphoma-2 (BCL-2) antiapoptotic proteins can overcome the evasion of apoptosis in cancer cells. BCL-2 inhibitors have evolved into an important means of treating cancers by inducing tumor cell apoptosis. As the most extensively investigated BCL-2 inhibitor, venetoclax is highly selective for BCL-2 and can effectively inhibit tumor survival. Its emergence and development have significantly influenced the therapeutic landscape of hematological malignancies, especially in chronic lymphocytic leukemia and acute myeloid leukemia, in which it has been clearly incorporated into the recommended treatment regimens. In addition, the considerable efficacy of venetoclax in combination with other agents has been demonstrated in relapsed and refractory multiple myeloma and certain lymphomas. Although venetoclax plays a prominent antitumor role in preclinical experiments and clinical trials, large individual differences in treatment outcomes have been characterized in real-world patient populations, and reduced drug sensitivity will lead to disease recurrence or progression. The therapeutic efficacy may vary widely in patients with different molecular characteristics, and key genetic mutations potentially result in differential sensitivities to venetoclax. The identification and validation of more novel biomarkers are required to accurately predict the effectiveness of BCL-2 inhibition therapy. Furthermore, we summarize the recent research progress relating to the use of BCL-2 inhibitors in solid tumor treatment and demonstrate that a wealth of preclinical models have shown promising results through combination therapies. The applications of venetoclax in solid tumors warrant further clinical investigation to define its prospects.

UNASSIGNED: This study aimed to improve the understanding of acute myeloid leukemia (AML) secondary to chronic lymphocytic leukemia (CLL), and to explore the sequence of occurrence and clonal origin of the two diseases.
UNASSIGNED: We reported a case of a 71-year-old man with a history of CLL. The patient was administrated with chlorambucil for 19 years and was admitted to our hospital due to fever. Then he was subjected with routine blood tests, bone marrow smear examination, flow cytometric immunophenotyping and cytogenetic analysis. A final diagnosis of AML-M2 secondary to CLL with -Y,del(4q),del(5q),-7,add(12p),der(17),der(18),-22,+mar was made. After rejecting the therapy with Azacitidine combined with B-cell lymphoma-2 (Bcl-2) inhibitor, the patient died of pulmonary infection.
UNASSIGNED: This case highlights the rare occurrence of AML secondary to CLL after prolonged chlorambucil therapy and the poor prognosis of such cases, underscoring the importance of enhanced assessment of these patients.

Multiple myeloma (MM) is an incurable malignancy. Venetoclax (VEN) shows a meaningful effect in MM patients who are relapsed or refractory (RR) to previous standard therapies.
This study aimed to assess the efficacy and safety of VEN-based treatments in RR MM patients.
Comprehensive studies were searched in PubMed, Embase, Web of Science and Cochrane library. Efficacy was assessed by overall response rate (ORR), strict complete response rate (sCR), complete response rate (CR), very good partial response rate (VGPR) and partial response rate (PR).
Seven studies containing 482 subjests were included. The pooled ORR, ≥ CR (sCR + CR), VGPR and PR were 68% (51%-85%), 24% (13%-35%), 25% (17%-34%) and 17% (11%-24%) respectively. Multi-drug treatments were superior to VEN ± dexamethasone (Dex) treatments in ORR (82% vs 42%, p = .003) and ≥ CR (36% vs 7%, p < 0.00001). Subgroup analysis indicated patients achieve higher ORR who harboring t(11;14) translocation or containing high BCL-2 expression.
VEN-containing regimens could be suggested as effective and safe treatments to RR MM patients with t(11;14) or high BCL-2 levels.

Acute myeloid leukemia (AML) is one of the most common hematological malignancies with high heterogeneity, characterized by a differentiating block at the early progenitor stage. The selective BCL-2 inhibitor, Venetoclax (Ven), has shown exciting clinical results in a certain group of AML patients. However, Ven alone is insufficient to reach an enduringly complete response, which leads to the concern of Ven resistance. Alternative combined therapies with Ven are demanded in AML. Here, we reported the synergistic effect and molecular mechanism of the enhancer of zeste homolog 2 (EZH2) inhibitor DZNeP with Ven in AML cells. Results showed that the combination of DZNeP with Ven significantly induces cell proliferation arrest compared to single-drug control in AML cells and primary samples, and CalcuSyn analysis showed their significant synergy. The combination also significantly promotes apoptosis and increases the expression of pro-apoptotic proteins. The whole transcriptome analysis showed that phosphoinositide-3-kinase-interacting protein1 (PIK3IP1), the PI3K/AKT/mTOR signaling suppressor, is upregulated upon DZNeP treatment. Moreover, EZH2 is upregulated but PIK3IP1 is downregulated in 88 newly diagnosed AML cohorts compared to 70 healthy controls, and a higher expression of EZH2 is associated with poor outcomes in AML patients. Particularly, the combination of DZNeP with Ven dramatically eliminated CD117 (c-KIT) (+) AML blasts, suggesting the effect of the combination on tumor stem cells. In summary, our data indicated that DZNeP increases the sensitivity of Ven in AML by affecting PI3K and c-KIT signaling in AML. Our results also suggested that the therapeutic targeting of both EZH2 and BCL-2 provides a novel potential combined strategy against AML.

Prevention of relapse is a major therapeutic challenge and an unmet need for patients with acute myeloid leukemia (AML). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in AML cells. When combined with azacitidine, it leads to prolonged overall survival and rapid, durable remissions in treatment-naive AML patients ineligible for intensive chemotherapy. VIALE-M is a randomized, double-blind, two-arm study to evaluate the safety and efficacy of venetoclax in combination with oral azacitidine (CC-486) as maintenance therapy in patients in complete remission with incomplete blood count recovery after intensive induction and consolidation therapies. The primary end point is relapse-free survival. Secondary outcomes include overall survival, minimal residual disease conversion and improvement in quality-of-life. Trial Registration Number: NCT04102020 (ClinicalTrials.gov).

CD47 expressed on cancer cells enables macrophage immune evasion. Blocking CD47 using anti-CD47 monoclonal antibodies (mAbs) is a promising strategy. The anti-CD47 mAb TJC4 has anti-tumor activity but lacks hematological toxicity. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor for B-cell malignancy, induces phosphatidylserine (PS) extracellular exposure, representing an \"eat-me\" signal for macrophages. The present study aimed to explore whether TJC4-Venetoclax combined therapy exerts synergistic anti-cancer properties in B-cell lymphoma. In vitro, flow cytometry and microscopy assessed whether TJC4 monotherapy or combination treatment could promote macrophage-mediated phagocytosis of tumor cells. Induced PS exposure on the cell membrane was measured using flow cytometry with Annexin V-FITC staining. In vivo, Venetoclax and TJC4\'s synergistic anti-tumor effects were evaluated. B cell lymphoma cell lines express high levels of CD47 and patients with diffuse large B cell lymphoma expressing CD47 have a worse clinical prognosis. TJC4 eliminates tumor cells via macrophage-mediated phagocytosis. In vitro and in vivo, the TJC4-Venetoclax combination increased phagocytosis significantly compared with either agent alone, showing synergistic phagocytosis, and displayed synergistic anti-cancer properties in B-cell lymphoma. Our results support the TJC4-Venetoclax combination as a promising therapy, and suppressing BCL-2 and CD47 simultaneously could represent a novel therapeutic paradigm for B-cell lymphoma.

Older acute myeloid leukemia patients usually experience a bleak outcome, especially those in the unfit group. For this unfit category, intensive chemotherapy and allogeneic stem cell transplantation are usually accompanied by higher early mortality, which results from higher risk genetic profiles and worse psychological and physiological conditions. The significant improvement in genetic technology recently has driven the appearance of several mutation-targeted therapies, such as FLT3, Bcl-2, IDH and Hedgehog pathway inhibitors and an anti-CD33 antibody-drug conjugate, which have changed enormously the therapeutic landscape of acute myeloid leukemia. This review describes the treatment dilemma of the unfit group and discusses the objective clinical data of each targeted drug and mechanisms of resistance, with a focus on combination strategies with fewer toxicities and abrogation of drug resistance.